This invention relates to substituted heteroanilide compounds which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (Nature Medicine 1996, 2, 1174-8). In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5.
T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases. Increased numbers or enhanced activation state of T cells, especially CD4+ T cells, have been demonstrated in the synovium of individuals with rheumatoid arthritis (M. J. Elliott and R. N. Maini, Int. Arch. Allergy Immunol. 104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C. J. Cofrigan and A. B. Kay, Immunol. Today 13:501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland, Crit. Rev. Clin. Lab. Sci. 32: 121-1827 1995), in psoriatic lesions (J. L. Jones, J. Berth-Jone, A. Fletcher and P. E. Hutchinson, J. Pathol. 174: 77-82, 1994) and in the fatty streaks of atherosclerosis (R. Ross, Annu. Rev. Physiol. 57: 791-804, 1995).
T cells, as well as other inflammatory cells, will migrate into tissues in response to the production of a variety of chemotactic factors. Among these factors are a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues. RANTES, which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is an 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors. The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser, Adv. Immunol. 55: 97-179, 1994: and J. J. Oppenheim, C. O. C. Zachariae, N. Mukaida and K. Matsushima, Annu. Rev. Immunol. 9: 617-648, 1991).
RANTES potently produces chemotaxis of T cells, basophils, eosinophils, monocytes and mast cells. RANTES was originally identified as gene product induced late after antigen activation of T-cells (T. J. Schall, J. Jongstra, B. J. Dyer, J. Jorgensen, et al., J. Immunol. 141:1018-1025, 1988), however, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include epithelial and endothelial cells (C. Stellato, L. A. Beck. G. A. Gorgone, D. Proud, et al., J. Immunol. 155: 410-418, 1995; and A. Marfaing-Koka, O. Devergne, G. Gorgone, A. Portier, et al., J. Immunol. 154: 1870-1878, 1994), synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick. T. J. Schall. et al., J. Biol. Chem. 268: 5834-5839, 1993) and dermal fibroblasts (M. Sticherling, M. Kupper, F. Koltrowitz, E. Bornscheuer, et al., J. Invest. Dermatol. 105: 585-591, 1995), mesangial cells (G. Wolf, S. Aberle. F. Thaiss, et al., Kidney Int. 44: 795-804, 1994) and platelets (Y. Koameyoshi, A. Dorschner, A. I. Mallet, E. Christophers, et al., J. Exp. Med. 176: 587-592, 1992). In these cells RANTES mRNA is rapidly upregulated in response to IL-1 or TNFa. Although RANTES mRNA is not usually detected in normal tissues (J. M. Pattison, P. J. Nelson, and A. M. Krensky. Clin. Immunother. 4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate. For example, RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J. M. Pattison, P. J. Nelson, and A. M. Krensky, Clin. Immunother. 4: 1-8, 1995; and K. C. Nadeau, H. Azuma and N. I. Tilney. Proc. Natl. Acad. USA 92: 8729-8733, 1995) in the skin of atopic dermatitis patients after exposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng, M. Humbert, et al., J. Exp. Med. 181: 2153-2159, 1995), and in endothelial cells of coronary arteries undergoing accelerated atherosclerosis after cardiac transplant (J. M. Pattison, P. J. Nelson, and A. M. Krensky, Clin. Immunother. 4: 1-8, 1995). Further, increased immunoreactive protein for RANTES has been detected in bronchoalveolar lavage fluid (R. Alam, J. York, M. Boyers, et al., Am. J. Resp. Crit. Care Med. 149: A951, 1994) and sputum from asthmatic individuals (C. M. Gelder, P. S. Thomas, D. H. Yates, I. M. Adcock, et al., Thorax 50: 1033-1037, 1995).
Several receptors have been identified that bind RANTES. In particular, CCR5, when expressed in either HEK 293 cells or CHO cells, binds RANTES. This receptor is expressed in T-cells and in monocytes and macrophages, immune/inflammatory cells which are important in the maintenance of a chronic inflammatory reaction. Pharmacological characterization of CCR5 indicates similarities to the RANTES binding site observed on isolated T cells. Therefore, antagonism of RANTES"" action on CCR5, as well as antagonism of other natural modulators of CCR5, should inhibit the recruitment and activation of T cells and macrophages into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders.
Since T cells express CCR5, selective receptor modulators of CCR5, particularly antagonists, are likely to provide beneficial effects in diseases including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans. Furthermore, since CD8+ T cells have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therapeutic in the treatment of COPD. Also, since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection.
Surprisingly, it has now been discovered that this class of non-peptide compounds, in particular substituted heteroanilide compounds of this invention, function as CCR5 receptor modulators, and therefore, have utility in the treatment and prevention of disease states mediated by CCR5 receptor mechanisms.
In one aspect, the present invention is to novel compounds of formula (I), or pharmaceutically active salts thereof, and their novel use in treating the above-mentioned CCR5-mediated disease states:
Ar-L-Exe2x80x83xe2x80x83Formula I
in which Ar represents a group of Formula (i) or (ii): 
xe2x80x83wherein:
the basic nitrogen in moiety E may be optionally quaternized with C1-6alkyl or is optionally present as the N-oxide;
P1 and P2 are independently phenyl, fused bicyclic aryl, a monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur, providing that at least one of P1 and P2 is a heterocyclic group;
P3 is a monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
L is a group of formula xe2x80x94C(xe2x95x90V)xe2x80x94DR6xe2x80x2xe2x80x94, xe2x80x94DR7xe2x80x2xe2x80x94C(xe2x95x90V)xe2x80x94, xe2x80x94CH2NHxe2x80x94, or xe2x80x94NHCH2xe2x80x94;
V is oxygen or sulfur;
D is nitrogen, carbon, or a CH group,
R1xe2x80x2, R2xe2x80x2, and R4xe2x80x2 are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, aryl, (CH2)dxe2x80x2NR8xe2x80x2R9xe2x80x2, (CH2)dxe2x80x2NR8xe2x80x2COR10xe2x80x2, (CH2)dxe2x80x2NR8xe2x80x2CO2R11xe2x80x2, (CH2)dxe2x80x2NR8xe2x80x2SO2R12xe2x80x2, (CH2)dxe2x80x2CONR13xe2x80x2R14xe2x80x2, hydroxyC1-6alkyl, C1-4alkoxyalkyl (optionally substituted by a C1-4alkoxy or hydroxy group), (CH2)dxe2x80x2CO2C1-6alkyl, (CH2)exe2x80x2OC(O)R15xe2x80x2, CR16xe2x80x2xe2x95x90NOR17xe2x80x2, CNR18xe2x80x2xe2x95x90NOR17xe2x80x2, COR19xe2x80x2, CONR13xe2x80x2R 14xe2x80x2, CONR13(CH2)fOC1-4alkyl. CONR13xe2x80x2(CH2)dxe2x80x2CO2R20xe2x80x2. CONHNR21xe2x80x2R22xe2x80x2, CONR13xe2x80x2SO2R23xe2x80x2, CO2R24xe2x80x2, cyano, trifluoromethyl, NR8xe2x80x2R9xe2x80x2, NR8xe2x80x2COR10xe2x80x2. NR25xe2x80x2CO(CH2)dxe2x80x2NR25xe2x80x2R26xe2x80x2, NR25xe2x80x2CONR25xe2x80x2R26xe2x80x2, NR8xe2x80x2CO2R11xe2x80x2,NR8xe2x80x2SO2R12xe2x80x2, Nxe2x95x90CNR25xe2x80x2NR25xe2x80x2R26xe2x80x2, nitro, hydroxy, C1-6alkoxy, hydroxy C1-6alkoxy, C1-6alkoxyC1-6alkoxy, OC(O)NR27xe2x80x2R28xe2x80x2, SR29xe2x80x2, SOR30xe2x80x2, SO2R30xe2x80x2. SO2NR31xe2x80x2R32xe2x80x2, halogen, C1-6alkanoyl, CO2(CH2)dxe2x80x2OR33xe2x80x2, or R1xe2x80x2 is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur,
R3xe2x80x2 and R5xe2x80x2 are independently hydrogen, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, hydroxyC1-6alkyl, C1-6alkylOC1-6alkyl, CONR34xe2x80x2R35xe2x80x2, CO2R36xe2x80x2, cyano, aryl, trifluoromethyl, NR37xe2x80x2R38xe2x80x2, nitro, hydroxy, C1-6alkoxy, C1-6alkanoyl, acyloxy, or halogen:
R16xe2x80x2, R17xe2x80x2, R18xe2x80x2, R19xe2x80x2, R20xe2x80x2, R21xe2x80x2, R22xe2x80x2, R25xe2x80x2, R26xe2x80x2, R29xe2x80x2, R33xe2x80x2, R34xe2x80x2, R35xe2x80x2, R36xe2x80x2, R37xe2x80x2, and R38xe2x80x2 are independently hydrogen or C1-6alkyl;
R6xe2x80x2 is hydrogen or C1-6alkyl, providing that D is nitrogen or a CH group;
R7xe2x80x2 is hydrogen or C1-6alkyl, providing that D is nitrogen or a CH group;
R8xe2x80x2 and R9xe2x80x2 are independently hydrogen or C1-6alkyl, or R8xe2x80x2 and R9xe2x80x2 together with the nitrogen to which they are attached, forms a 5- to 6-membered heterocyclic ring, which may optionally be substituted by an oxo group, and when there are six members may optionally contain in the ring one oxygen or one sulfur atom;
R10xe2x80x2 is hydrogen, C1-6alkyl, or C1-4alkoxyalkyl;
R11xe2x80x2, R23xe2x80x2, and R30xe2x80x2 are independently C1-6alkyl;
R12xe2x80x2 is C1-6alkyl or phenyl;
R13xe2x80x2 and R14xe2x80x2 are independently hydrogen or C1-6alkyl, or R13xe2x80x2 and R14xe2x80x2 together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom;
R15xe2x80x2 is C1-4alkyl, optionally substituted by C1-6alkoxy;
R24xe2x80x2 is hydrogen or C1-6alkyl optionally substituted with one or two substituents selected from C1-6alkyl, C1-6alkoxy, hydroxy, or NR8xe2x80x2R9xe2x80x2;
R27xe2x80x2 and R28xe2x80x2 are independently hydrogen or C1-6alkyl, or R27xe2x80x2 and R28xe2x80x2 together with the nitrogen to which they are attached form a 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom;
R31xe2x80x2 and R32xe2x80x2 are independently hydrogen or C1-6alkyl, or R31xe2x80x2 and R32xe2x80x2 together with the nitrogen to which they are attached form 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or one sulfur atom;
axe2x80x2 and bxe2x80x2 are independently 1,2, or 3;
cxe2x80x2 is 0, 1, or 2;
dxe2x80x2 is 1, 2, 3, or 4;
exe2x80x2 is 0, 1, 2, or 3;
fxe2x80x2 is 1, 2, or 3;
E represents (a): 
xe2x80x83in which
B is oxygen, S(O)c, CR7xe2x95x90CR8, or CR7R8, or B is NR9;
R1 and R2 are independently hydrogen or C1-6alkyl; alternatively B(CR1R2)a is OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2;
R3 and R4 are independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1-6alkyl, aryl, CONR10R11, NR10R11, hydroxy, OCOR12, NHCOC0-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R13, and NHCO2R14;
R5 is hydrogen, C1-6alkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, C1-6alkoxy, benzyloxy, OCH2CO2C1-6alkyl, OCF3, S(O)dR19, SO2NR20R21 or halogen;
R6 is hydroge, C1-6alkyl, aryl, trifluoromethyl, hydroxy, C1-6alkoxy or halogen, or R6 taken together with R6xe2x80x2 forms a group D where D is (CR22R23)e or D is (CR22R23)f-G where G is oxygen, sulfur or CR22xe2x95x90CR23, CR22xe2x95x90N, xe2x95x90CR22O, xe2x95x90CR22S, or xe2x95x90CR22-NR23;
R7, R8, R10, R11, R12, R15, R16, R17, R20, R21, R22, and R23 are independently hydrogen or C1-6alkyl;
R9 is hydrogen, C1-6alkyl, or phenylC1-6alkyl;
R13, R14, R18, and R19 are independently C1-6alkyl;
a is 1, 2, 3, or 4;
b is 1 or 2;
c and d are independently 0, 1 or 2;
e is 2, 3 or 4,
f is 0, 1, 2 or 3:
alternatively. E represents (b): 
R24, R25, R26, R27, R28, R29, R31, and R32 are independently hydrogen or C1-6alkyl;
R30 is hydrogen, C1-6alkyl, or C3-7cycloalkyl;
R33 is hydrogen, C1-6alkyl, trifluoromethyl, hydroxy, or halogen, or R33 and R6xe2x80x2 together form a group xe2x80x94Kxe2x80x94 where K is (CR34R35)i or K is (CR34R35)j-M and M is oxygen, sulfur, CR34xe2x95x90CR35, CR34xe2x95x90N, or Nxe2x95x90N:
J is oxygen, CR36R37, or NR38, or J is a group S(O)k 
R34, R35, R36, R37, and R38 are independently hydrogen or C1-6alkyl;
g is 1, 2, or 3;
h is 1, 2 or 3;
i is 2, 3, or 4;
j is 0, 1, 2, or 3;
k is 0, 1 or 2;
alternatively, E represents (c): 
xe2x80x83in which:
Q is oxygen, S(O)n, CR44xe2x95x90CR45, CR44R45, or Q is NR46;
R39 and R40 are independently hydrogen or C1-6alkyl;
R41 is a group of formula (d): 
or R41 is a group of formula (e): 
R42 is hydrogen, C1-6alkyl, aryl, CN, CONR48R49, CO2R50, trifluoromethyl, NHCO2R51, hydroxy, C1-6alkoxy, benzyloxy, OCH2CO2C1-6alkyl, OCF3, S(O)sR52, SO2NR53R54, or halogen;
R43 is hydrogen or R43 together with R6xe2x80x2 forms a group R where R is CR55xe2x95x90CR56, CR55xe2x95x90CR56CR55R56, or (CR55R56)t;
R44, R45, R46, R48, R49, R50, R53, R54, R55, and R56 are independently hydrogen or C1-6alkyl;
R47 is hydrogen, C1-6alkyl, or C3-7 cycloalkyl;
R51 and R52 are independently C1-6alkyl;
1 is 0, 1, 2, or 3;
m is 1 or 2;
n is 0, 1, or 2
o, p, and q are independently integers having the value 1, 2, or 3;
r is 0, 1, 2, or 3;
s is 0, 1, or 2;
t is 2 or 3;
alternatively, E represents (f): 
R57 and R58 are independently hydrogen or C1-6alkyl;
R59 and R60 are independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1-6alkyl, aryl, CONR61R62, NR61R62, hydroxy, OCOR63, NHCOC0-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R64, and NHCO2R65;
T is xe2x80x94(CR66R67)vxe2x80x94 or xe2x80x94O(CR66R67)wxe2x80x94;
W is oxygen, S(O)x, NR68, or W is CR69xe2x95x90CR70 or CR69R70;
R61, R62, R63, R66, R67 R68, R69, and R70 are independently hydrogen or C1-6alkyl;
R64 and R65 are independently C1-6alkyl;
u is 1 to 4;
v is 2 or 3;
w is 1, 2, or 3;
x is 0, 1 or 2;
alternatively, E represents a group (g): 
R71 is an optionally substituted 5 to 7-membered saturated or partially saturated heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur or R71 is an optionally substituted 6,6 or 6,5 bicyclic ring containing a nitrogen atom and optionally a further heteroatom selected from oxygen, nitrogen or sulfur;
R72 is hydrogen, C1-6alkyl, aryl, CN, CONR74R75, CO2R76, trifluoromethyl, NHCO2R77, hydroxy, C1-6alkoxy, benzyloxy, OCH2CO2C1-6alkyl, OCF3, S(O)zR78, SO2NR79R80, or halogen;
R73 is hydrogen, C1-6alkyl, hydroxy, C1-6alkoxy or halogen, or R73 and R6xe2x80x2 taken together from a group xe2x80x94Xxe2x80x94 where X is (CR81R82)aa or X is (CR81R82)abxe2x80x94Y and Y is oxygen, sulfur or CR81xe2x95x90CR82;
R74, R75, R76, R79, R80, R81, and R82 are independently hydrogen or C1-6alkyl;
R77 and R78are independently C1-6alkyl;
y is 1 or 2;
z is 0, 1, or 2;
aa is 2, 3 or 4;
ab is 0, 1, 2 or 3;
alternatively, E represents group (h); 
R83 and R84 are independently hydrogen or C1-6alkyl;
R85 and R86 are independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1-6alkyl, aryl, CONR88R89, NR90R91, hydroxy, OCOR92, NHCOC0-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2R93, and NHCO2R94;
R87 is hydrogen or C1-6alkyl, C1-6alkoxy, or halogen, or R87 together with R6xe2x80x2 forms a group xe2x80x94AAxe2x80x94 where AA is (CR95R96)ad or AA is (CR95xe2x95x90CR96)aexe2x80x94AB and AB is oxygen, sulfur, CR95xe2x95x90CR96, CR95xe2x95x90N, CR95NR96 or Nxe2x95x90N;
Z is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur;
R88, R89, R90, R91, R92, R95, and R96 are independently hydrogen or C1-6alkyl;
R93 and R94 are independently C1-6alkyl;
ac is 0 to 4;
ad is 1, 2 or 3;
ae is 0, 1, or 2;
alternatively, E represents group (i): 
R97 and R98 are independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1-6alkyl, aryl, CONR102R103, NR104R105, hydroxy, OCOR106, NHCOC0-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2 R107, and NHCO2R108;
R99 and R100 are independently hydrogen or C1-6alkyl;
R101 is hydrogen or C1-6alkyl or R101 and R6xe2x80x2 together form a group xe2x80x94ADxe2x80x94 where AD is (CR109R110)ai or AD is (CR109R110)aj-AE and AE is oxygen, sulfur or CR109xe2x95x90CR110;
AC is oxygen, CR111R112 or NR113 or AC is a group S(O)ak;
R102, R103, R104, R105, R106, R109, R110, R111, R112, and R113 are independently hydrogen or C1-6alkyl;
R107 and R108 are independently C1-6alkyl:
af is 0, 1, 2, 3, or 4;
ag is 1, 2, or 3;
ah is 1, 2, 3 or 4;
ai is 2, 3 or 4;
aj is 0, 1, 2, or 3; and
ak is 0, 1 or 2.
It has now been discovered that substituted anilides of formula (I) are CCR5 receptor modulators. It has also now been discovered that selective inhibition of CCR5 receptor mechanisms by treatment with the receptor modulators of formula (I), or a pharmaceutically acceptable salt thereof, represents a novel therapeutic and preventative approach to the treatment of a variety of disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, sarcoidosis and other fibrotic disease, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans (xe2x80x9cCCR5-mediated diseasesxe2x80x9d). Also, since CCR5 is a co-receptor for the entry of HIV into cells. selective receptor modulators may be useful in the treatment of HIV infection.
The term xe2x80x9calkylxe2x80x9d is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
The terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9ccyclic alkylxe2x80x9d are used herein at all occurrences to mean cyclic radicals, preferably comprising 3 to 7 carbon atoms which may be mono- or bicyclo-fused ring systems which may additionally include unsaturation, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d are used interchangeably herein at all occurrences to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
The term xe2x80x9cheterocyclic ringxe2x80x9d is used herein at all occurrences to mean a saturated or partially saturated 5-, 6-, or 7-membered ring system (unless the cyclic ring system is otherwise limited) in which the ring system contains one to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which ring system may be optionally substituted with C1-6alkyl or C3-7cycloalkyl. Examples of such rings include, but are not limited to, piperidine, tetrahydropyridine, and piperazine. When the heterocyclic ring is fused to a phenyl group, the term xe2x80x9cheterocyclic ringxe2x80x9d, together with the phenyl ring to which it is fused, forms a ring which includes, but is not limited to, dihydro-1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline, which may be optionally substituted by C1-6alkyl or oxo.
The term xe2x80x9c6,6 or 6,5 bicyclic ringxe2x80x9d means a 6,6 or 6,5-bicyclic ring system containing a nitrogen atom and optionally a further heteroatom selected from nitrogen, oxygen, or sulfur, which ring system may be optionally substituted with C1-6alkyl. Examples of such ring systems include, but are not limited to, tropane, isoquinuclidine and granatane rings.
The term xe2x80x9cCCR5 mediated disease statexe2x80x9d is used herein at all occurrences to mean any disease state which is mediated (or modulated) by CCR5.
The term xe2x80x9cmonocyclic heterocyclic ringxe2x80x9d is used herein at all occurrences to mean a single aromatic ring of 5 to 7 members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur represented by P1 and/or P2 include thienyl, furyl, pyrrolyl, and pyridyl.
The term xe2x80x9cfused bicyclic heterocyclic ringxe2x80x9d is used herein at all occurrences to mean a fused bicyclic aromatic ring system of 8 to 11-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur include indole, benzofuran, benzothiophene, quinoline, and isoquinoline rings.
Suitably, pharmaceutically acceptable salts of formula (I) include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, palmitate, salicylate, and stearate.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like, are equivalent to the unsolvated forms for purposes of this invention.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. The stereocenters may be of any combination of R and S configuration, for example, (R,R), (R,S), (S,S) or (S,R). All of these compounds are within the scope of the present invention.
For the compounds of formula (I) various embodiments are as follows. It will be understood that the basic nitrogen in moiety E may be optionally quaternized with C1-6alkyl or is optionally present as the N-oxide.
wherein:
P1 and P2 are suitably independently phenyl, fused bicyclic aryl, a monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur, providing that at least one of P1 and P2 is a heterocyclic group. Preferably, P1 and P2 are phenyl, pyrrolyl, thienyl, thiazolyl, 1,2,3-triazolyl, pyridyl, and benzodioxanyl, providing that at least one of P1 or P2 is a heterocyclic group. More preferably, P1 and P2 are phenyl, thienyl, and benzodioxanyl, providing that at least one of P1 and P2 is a heterocyclic group.
P3 is suitably a monocyclic heterocyclic ring of 5- to 7-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, or a fused bicyclic heterocyclic ring of 8 to 11-members containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur. P3 is preferably thienyl, pyridyl, indolyl, benzofuranyl, benzothienyl, and benzopyranyl. More preferably, P3 is indolyl, benzofuranyl, and benzopyranyl.
When R1xe2x80x2 is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur, suitable heterocyclic rings include aromatic groups such as thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, and dioxanyl. Saturated and partially saturated rings are also within the scope of the invention, in particular rings including an oxo or thioxo moiety such as lactams and thiolactams. Suitably, the heterocyclic ring can be linked to the remainder of the molecule via a carbon atom, or, when present, a nitrogen atom. Suitable substituents for these rings include one to two of R3xe2x80x2.
L is a suitably group of formula xe2x80x94C(xe2x95x90V)xe2x80x94DR6xe2x80x2xe2x80x94, xe2x80x94DR7xe2x80x2xe2x80x94C(xe2x95x90V)xe2x80x94, xe2x80x94CH2NHxe2x80x94, or xe2x80x94NHCH2xe2x80x94. L is preferably xe2x80x94C(xe2x95x90V)xe2x80x94DR6xe2x80x2xe2x80x94.
V is suitably oxygen or sulfur. V is preferably oxygen.
D is suitably nitrogen, carbon, or a CH group. D is preferably nitrogen.
R1xe2x80x2, R2xe2x80x2, and R4xe2x80x2 are suitably independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, aryl, (CH2)nxe2x80x2NR8xe2x80x2R9xe2x80x2, (CH2)dxe2x80x2NR8xe2x80x2COR10xe2x80x2, (CH2)nxe2x80x2NR8xe2x80x2CO2R11xe2x80x2, (CH2)dxe2x80x2NR8xe2x80x2SO2R12xe2x80x2, (CH2)dxe2x80x2CONR13xe2x80x2R14xe2x80x2, hydroxyC1-6alkyl, C1-4alkoxyalkyl (optionally substituted by a C1-4alkoxy or hydroxy group), (CH2)dxe2x80x2CO2C1-6alkyl, (CH2)exe2x80x2OC(O)R15xe2x80x2, CR16xe2x80x2xe2x95x90NOR17 xe2x80x2, CNR18xe2x80x2xe2x95x90NOR17xe2x80x2, COR19xe2x80x2, CONR13xe2x80x2R14xe2x80x2, CONR13xe2x80x2(CH2)fOC1-4alkyl, CONR13 xe2x80x2(CH2)dxe2x80x2CO2R20xe2x80x2, CONHNR21 xe2x80x2R22xe2x80x2, CONR13xe2x80x2SO2R23xe2x80x2, CO2R24xe2x80x2, cyano, trifluoromethyl, NR8xe2x80x2R9xe2x80x2, NR8xe2x80x2COR10xe2x80x2, NR25xe2x80x2CO(CH2)dxe2x80x2NR25xe2x80x2R26xe2x80x2, NR25xe2x80x2CONR25xe2x80x2R26xe2x80x2, NR8xe2x80x2CO2R11xe2x80x2, NR8xe2x80x2SO2R12xe2x80x2,
Nxe2x95x90CNR25xe2x80x2NR25xe2x80x2R26xe2x80x2, nitro, hydroxy, C1-6alkoxy, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkoxy, OC(O)NR27xe2x80x2R28xe2x80x2, SR29xe2x80x2, SOR30xe2x80x2, SO2R30xe2x80x2, SO2NR31 xe2x80x2R32xe2x80x2, halogen, C1-6alkanoyl, CO2(CH2)dxe2x80x2OR33xe2x80x2, or R1xe2x80x2 is an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur. Preferably, R1xe2x80x2, R2xe2x80x2, and R4xe2x80x2 are hydrogen, C1-6alkyl, trifluoromethyl, or halogen.
R3xe2x80x2 and R5xe2x80x2 are suitably independently hydrogen, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, hydroxyC1-6alkyl, C1-6alkylOC1-6akyl, CONR34xe2x80x2R35xe2x80x2, CO2R36xe2x80x2, cyano, aryl, trifluoromethyl, NR37xe2x80x2R38xe2x80x2, nitro, hydroxy, C1-6alkoxy, C1-6alkanoyl, acyloxy, or halogen. Preferably, R3xe2x80x2 and R5xe2x80x2 are hydrogen, C1-6alkyl, C1-6alkoxy, or halogen.
R16xe2x80x2, R17xe2x80x2, R18xe2x80x2, R19xe2x80x2, R20xe2x80x2, R21xe2x80x2, R22 xe2x80x2, R25xe2x80x2, R26xe2x80x2, R29xe2x80x2, R33xe2x80x2, R34xe2x80x2, R35xe2x80x2, R36xe2x80x2, R37xe2x80x2, and R38xe2x80x2 are suitably independently hydrogen or C1-6alkyl.
R6xe2x80x2 is suitably hydrogen or C1-6alkyl, providing that D is nitrogen or a CH group. Preferably, R6xe2x80x2 is hydrogen.
R7xe2x80x2 is suitably hydrogen or C1-6alkyl, providing that D is nitrogen or a CH group.
R8xe2x80x2 and R9xe2x80x2 are suitably independently hydrogen or C1-6alkyl, or R8xe2x80x2 and R9xe2x80x2 together with the nitrogen to which they are attached, forms a 5- to 6-membered heterocyclic ring, which may optionally be substituted by an oxo group, and, when there are six members, may optionally contain in the ring one oxygen or one sulfur atom.
R10xe2x80x2 is hydrogen, C1-6alkyl, or C1-4alkoxyalkyl.
R11xe2x80x2, R23xe2x80x2, and R30xe2x80x2 are independently C1-6alkyl.
R12xe2x80x2 is C1-6alkyl or phenyl.
R13xe2x80x2 and R14xe2x80x2 are independently hydrogen or C1-6alkyl, or R13xe2x80x2 and R14xe2x80x2 together with the nitrogen to which they are attached form a 5- to 6-membered saturated heterocyclic ring which, when there are 6 ring members, may optionally contain in the ring one oxygen or one sulfur atom.
R15xe2x80x2 is C1-4alkyl, optionally substituted by C1-6alkoxy.
R24xe2x80x2 is hydrogen or C1-6alkyl optionally substituted with one or two substituents selected from C1-6alkyl, C1-6alkoxy, hydroxy, or NR8xe2x80x2R9xe2x80x2.
R27xe2x80x2 and R28xe2x80x2 are independently hydrogen or C1-6alkyl, or R27xe2x80x2 and R28xe2x80x2 together with the nitrogen to which they are attached form a 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom.
R31xe2x80x2 and R32xe2x80x2 are independently hydrogen or C1-6alkyl, or R31xe2x80x2 and R33xe2x80x2 together with the nitrogen to which they are attached form 5- to 6-membered heterocyclic ring which, when there are six ring members, may optionally contain in the ring one oxygen or sulfur atom.
axe2x80x2 and bxe2x80x2 are independently 1, 2, or 3.
cxe2x80x2 is 0, 1, or 2.
dxe2x80x2 is 1, 2, 3, or 4.
exe2x80x2 is 0, 1, 2, or 3.
fxe2x80x2 is 1, 2, or 3.
E suitably represents (a): 
xe2x80x83in which
B is suitably oxygen, S(O)c, CR7xe2x95x90CR8, or CR7R8, or B is NR9, B is preferably CR7R8, or oxygen. More preferably, B is CH2 or oxygen.
R1 and R2 are suitably independently hydrogen or C1-6alkyl; alternatively B(CR1R2)a is OCR1R2CR1(OH)CR1R2 or OCR1R2CR1(OCOCH3)CR1R2. Preferably, R1 and R2 are hydrogen.
R3 and R4 are suitably independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur, where optional substituents include C1-6alkyl, aryl, CONR10R11, NR10R11, hydroxy, OCOR12, NHCOC0-6alkyl where alkyl is optionally substituted by OH, NHCOCF3, NHSO2 R13, and NHCO2R14. Preferably R3 and R4 are both C1-6alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring which may contain an additional heteroatom selected from oxygen, nitrogen or sulfur. More preferably, R3 and R4 are C3-6alkyl, or together with the nitrogen to which they are attached form a 6-membered ring, optionally substituted with one or more of C1-6alkyl, N-acetamido, or hydroxy. Most preferably, R3 and R4 are isopropyl or R3 is isopropyl and R4 is tert-butyl, or together with the nitrogen to which they are attached are 1-(2,2,6,6-tetramethylpiperidinyl), 1-(4-acetamido-2,2,6,6-tetramethylpiperidinyl), 1-(4-hydroxy-2,2,6,6-tetramethylpiperidinyl), or 1-(4-hydroxy-2,2,4,6,6-pentamethylpiperidinyl).
Preferably, B-(CR1R2)a-NR3R4 is ortho to R5, meta to L, and para to R6, and R5 is para to L.
R5 is suitably hydrogen, C1-6alkyl, aryl, CN, CONR15R16, CO2R17, trifluoromethyl, NHCO2R18, hydroxy, C1-6alkoxy, benzyloxy, OCH2CO2C1-6alkyl, OCF3, S(O)dR19, SO2NR20R21, or halogen. R5 is preferably C1-6alkoxy, SC1-6alkyl or halogen; more preferably methoxy, methylthio or iodo, most preferably methoxy. When R5 is methoxy, it is preferably para to L.
R6 is suitably hydrogen, C1-6alkyl, aryl, trifluoromethyl, hydroxy, C1-6alkoxy, or halogen, or R6 taken together with R6xe2x80x2 forms a group D where D is (CR22R23)e or D is (CR22R23)f-G where G is oxygen, sulfur, or CR22xe2x95x90CR23, CR22xe2x95x90N, xe2x95x90CR22O, xe2x95x90CR22S, or xe2x95x90CR22xe2x80x94NR23. Preferably, R6 is hydrogen.
R7, R8, R10, R11, R15, R16, R17, R20, R21, R22, and R23 independently hydrogen or C1-6alkyl.
R9 is hydrogen, C1-6alkyl, or phenylC1-6alkyl.
R12, R13, R14, R18, and R19 are independently C1-6alkyl.
a is suitably 1, 2, 3, or 4. Preferably, a is 2 or 3, more preferably, a is 2 or 3 when B is oxygen and a is 2 when B is CH2, most preferably, a is 2 when B is oxygen.
b is suitably 1 or 2. Preferably, b is 1.
c and d are suitably independently 0, 1, or 2.
e is suitably 2, 3, or 4.
f is suitably 0, 1, 2, or 3.
alternatively, E suitably represents (b): 
R24, R25, R26, R27, R28, R29, R31, and R32 are suitably independently hydrogen or C1-6alkyl. R24, R25, R26, R27, R28, R29, R31, and R32 are preferably hydrogen.
R30 is suitably hydrogen, C1-6alkyl, or C3-7cycloalkyl. Preferably, R30 is C1-6alkyl, more preferably, R30 is C3-6alkyl, most preferably, R30 is isopropyl.
R33 is suitably hydrogen, C1-6alkyl, trifluoromethyl, hydroxy or halogen, or R33 and R6xe2x80x2 together form a group xe2x80x94Kxe2x80x94 where K is (CR34R35)i or K is (CR34R35)j xe2x80x94M and M is oxygen, sulfur, CR34xe2x95x90CR35, CR34xe2x95x90N, or Nxe2x95x90N. Preferably, R33 is hydrogen.
J is suitably oxygen, CR36R37, or NR38, or J is a group S(O)k. Preferably, J is oxygen. Preferably, J is para to L.
R34, R35, R36, R37, R38 are suitably independently hydrogen or C1-6alkyl.
g is suitably 1, 2,or 3. Preferably, g is 2 or 3, more preferably 2.
h is suitably 1, 2,or 3. Preferably, h is 1.
i is suitably 2, 3, or 4.
j is suitably 0, 1, 2, or 3.
k is suitably 0, 1 or 2.
A preferred subgenus of the compounds of formula (I) are compounds of formula (Ia) and formula (Ib) in which R1xe2x80x2, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2, R5xe2x80x2, p1, p2, p3, axe2x80x2, bxe2x80x2, cxe2x80x2, L, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, J, g, and h are define above: 
Among the preferred compounds of the invention are the following compounds:
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-5-(4-pyridinyl)-2-furancarboxamide;
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-5-(4-pyridyl)-thiophene-2-carboxamide;
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-5-(4-pyridinyl)-3-furancarboxamide;
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-3-methyl-4-(3-thienyl)-benzamide dioxalate;
4-Methoxy-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-5-(4-pyridinyl)-3-thiophenecarboxamide;
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4-(2-thienyl)-3-methylbenzamide oxalate;
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4-(4-phenyl-2-thiazolyl)benzamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-(1-pyrrolyl)pyridin-3-carboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-thiophenecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3-pyridinecarboxamide;
6-Chloro-N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3-pyridinecarboxamide;
5-Bromo-N-[3-[2-[bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3-pyridinecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-thiophenecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(3-pyridinyl)benzamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2-pyridinyl)benzamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2-thiazolyl)-benzamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-6-phenyl-3-pyridinecarboxamide:
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(4-pyridinyl)benzamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-phenyl-2-pyridinecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3-(2-thienyl)benzamide:
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2-thienyl)benzamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-phenyl-2-thiophenecarboxamide:
N-[1xe2x80x2-Isopropyl-spiro[benzofuran-3(2H),4xe2x80x2-piperidin]-5-yl)-2-(2,3-dihydro-1,4-benzodioxan-2-yl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-5-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-thiazolecarboxamide;
N-[3-[2-(Dimethylamino)ethoxy]-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-thiazolecarboxamide;
(+)-N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-thiazolecarboxamide;
(xe2x88x92)-N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(3-bromo-2-thienyl)-4-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-(3-bromo-2-thienyl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-2-(3-bromo-2-thienyl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-methyl-5-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy)-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-methyl-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-methyl-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-phenyl-4-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-phenyl-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-2-phenyl-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-methyl-2-phenyl-5-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-4-methyl-2-phenyl-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-4-methyl-2-(4-chlorophenyl)-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(4-chlorophenyl)-5-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-(4-chlorophenyl)-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-methyl-2-[3-(trifluoromethyl)phenyl]-5-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-4-methyl-2-[3-(trifluoromethyl)phenyl]-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-4-methyl-2- [3-(trifluoromethyl)phenyl]-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-[2-chloro-4-(trifluoromethyl)phenyl]-4-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-[2-chloro-4-(trifluoromethyl)phenyl]-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-2-[2-chloro-4-(trifluoromethyl)phenyl]-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(2,3-dichlorophenyl)4-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-(2,3-dichlorophenyl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-2-2,3-dichlorophenyl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-[3-(trifluoromethyl)phenyl]-4-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-[3-(trifluoromethyl)phenyl]-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-2-[3-(trifluoromethyl)phenyl]-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-methyl-2-pyrazinyl-5-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-4-methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-methyl-2-(4-chlorophenyl)-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-3-chloro-benzo[b]thiophene-2-carboxamide;
N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-3-chloro-benzo[b]thiophene-2-carboxamide;
N-[3-[3-[Bis(1-methylethyl)amino]propoxy]-4-methoxyphenyl]-3-chloro-benzo[b]thiophene-2-carboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-6-chloro-2H-1-benzopyran-3-carboxamide;
N-[3-[3-[Bis(1-methylethyl)amino]propyl]-4-methoxyphenyl]-6-chloro-2H -1-benzopyran-3-carboxamide;
N-[3-[3-[Bis(1-methylethyl)amino]propoxy]-4-methoxyphenyl]-6-chloro-2H-1-benzopyran-3-carboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy ]-4-methoxyphenyl]-5-chloro-1H-indole-2-carboxamide; and
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-chloro-2-benzofurancarboxamide.
Among the more preferred compounds of the invention are the following compounds:
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-(2-thienyl)benzamide;
N-[3-[2-(Diisopropylamino)ethoxy]-4-methoxyphenyl]-5-phenyl-2-thiophenecarboxamide;
N-[1xe2x80x2-Isopropyl-spiro[benzofuran-3(2H),4xe2x80x2-piperidin]-5-yl)-2-(2,3-dihydro-1,4-benzodioxan-2-y])-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-thiazolecarboxamide;
(+)-N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-thiazolecarboxamide;
(xe2x88x92)-N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-6-chloro-2H-1-benzopyran-3-carboxamide;
N-[3-[3-[Bis(1-methylethyl)amino]propoxy]-4-methoxyphenyl]-6-chloro-2H-1-benzopyran-3-carboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-chloro-1H-indole-2-carboxamide; and
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-chloro-2-benzofurancarboxamide.
Among the compounds specifically excluded from the scope of this invention are the following compounds:
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-3-methyl4-(4-pyridinyl)benzamide;
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4-(4-pyridinyl)benzamide dioxalate;
N-[4-Methoxy-3-(1-piperazinyl)phenyl]-3-methyl-4-(4-pyridinyl)benzamide;
N-[4-Methoxy-3-(4-ethyl-1-piperazinyl)phenyl]-3-methyl-4-(4-pyridinyl)benzamide oxalate;
N-[4-Methoxy-3-(4-benzyl 1-piperazinyl)phenyl]-3-methyl4-(4-pyridinyl)benzamide oxalate;
N-[4-(1-Methyl-3-piperidinyl)methoxyphenyl]-3-methyl-4-(4-pyridinyl)benzamide;
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-5-(2-pyridinyl)-2-thiophenecarboxamide oxalate;
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4-(4-methoxyphenyl-2-thiazolyl)benzamide;
N-[3-[2-(Dimethylamino)ethoxy]-4-methoxyphenyl]-3-methyl-4-(4-pyridinyl)benzamide;
N-[4-Methoxy-3-(4-methyl-1-piperazinyl)phenyl]-5-(3-pyridinyl)-3-thiazolecarboxamide;
1xe2x80x2-Methyl-5- {4-[2-methyl-6-(2-oxopyrrollidin-1-yl)pyrid-3-yl]benzoyl}-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4xe2x80x2-piperidine]hydrochloride;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-5-nitro-2-furancarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-furancarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-5-nitro-2-furancarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-furancarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-3-pyridinecarboxamide;
6-Chloro-N-[3-[2-(diethylamino)ethoxy]-4-methoxyphenyl]-3-pyridinecarboxamide;
5-Bromo-N-[3-[2-(diethylamino)ethoxy]-4-methoxyphenyl]-3-pyridinecarboxamide;
N-[3-[2-(Dimethylamino)ethoxy]-4-methoxyphenyl]-5-methyl-2-phenyl-2H-1,2,3-triazole4-carboxamide;
N-[3-[2-(Dimethylamino)ethoxy]-4-methoxyphenyl]-2-thiophenecarboxamide;
N-[3-[2-(Dimethylamino)ethoxy]-4-methoxyphenyl]-5-nitro-2-furancarboxamide;
N-[3-[2-(Dimethylamino)ethoxy]-4-methoxyphenyl]-2-furancarboxamide;
6-Chloro-N-[3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl]-3-pyridinecarboxamide;
5-Bromo-N-[3-[2-(dimethylamino)ethoxy]-4-methoxyphenyl]-3-pyridinecarboxamide.
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-phenyl]-4-methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-(4-methyl-1,2,3-thiadiazol-5-yl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-4-methyl-2-phenyl-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-methyl-2-(2-pyridinyl)-5-thiazolecarboxamide,
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-2-(2,3-dichlorophenyl)-4 -thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-methyl-2-(2-pyrazinyl)thiazole-5-carboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-methyl-2-(3-pyridinyl)4-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-4-methyl-2-(3-pyridinyl)-4-thiazolecarboxamide:
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-4-methyl-2-(3-pyridinyl)-4-thiazolecarboxamide:
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(4-methyl-1,2,3-thiadiazol-5-yl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-2-(4-methyl-1,2,3-thiadiazol-5-yl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(4-chlorophenyl)-4-methyl-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-phenyl]-2-(4-chlorophenyl)-4-methyl-5-thiazolecarboxamide;
N- [3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-2-(4-pyridinyl)-4-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-2-(4-pyridinyl)-4-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-2-(4-pyridinyl)-4-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-4-methyl -2-(3-pyridinyl)-5-thiazolecarboxamide;
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]-4-methoxyphenyl]-4-methyl-2-(4-pyridinyl)-5-thiazolecarboxamide;
N-[3-[2-(Diethylamino)ethoxy]-4-methoxyphenyl]-4-methyl-2-(4-pyridinyl)-5-thiazolecarboxamide; and
N-[3-[2-[Bis(1-methylethyl)amino]ethoxy]phenyl]-4-methyl-2-(4-pyridinyl)-5-thiazolecarboxamide.
A subgenus of formula (I) wherein E is (a); B is meta to L: Bxe2x80x94(CR1R2)axe2x80x94NR3R is xe2x80x94(CH2)3N(CH3)(C0-3alkyl); R5 is hydrogen, methyl, hydroxy, C1-3alkoxy, halogen; R6 is hydrogen, hydroxy, methoxy; L is CONH, NHCO or NHCH2; Ar is (i); R3xe2x80x2 is hydrogen; P1 is phenyl and P2 is attached in the 4-position; P2 is 2-furyl, 2-thienyl, imidazol-4-yl, 1,2,4-triazol-3-yl, 2-, 3-, or 4-pyridinyl; R1xe2x80x2 and R2xe2x80x2 are independently hydrogen, methyl, hydroxymethyl, 1-(hydroxy)ethyl, formyl, acetyl, carboxamido, carboxy, carbomethoxy; R3xe2x80x2 is hydrogen, has been described in GB 2276163, published Sep. 21, 1994, and GB 2276164, published Sep. 21, 1994; as 5-HT antagonists.
A compound of formula (I) wherein: E is (a); B is meta to L; Bxe2x80x94(CR1R2axe2x80x94NR3R is xe2x80x94Oxe2x80x94(CH2)2N(CH3)2; R5 is iodo; R6 is hydrogen; L is CONH; Ar is (ii); R4xe2x80x2 and R5xe2x80x2 are hydrogen; P3 is 4-quinolinyl has been described in international patent application number WO 98/50343, published Nov. 12, 1998, as a 5-HT receptor antagonist.
A subgenus of formula (I) wherein: E is (b); R24, R25, R26-29, R31-32 are hydrogen; R30 is hydrogen, methyl; J is para to L; J is oxygen; g is 2; h is 1, R33 and R6xe2x80x2 together are xe2x80x94(CH2)2xe2x80x94; Ar is (i); P2 is phenyl and P1 is attached at the 4-position; P1 is 3-pyridinyl; R1xe2x80x2 is 2-oxo-1-pyrrolidinyl, 1,3,4-oxadiazol-2-yl; R2xe2x80x2 is methyl; R3xe2x80x2 is hydrogen has been described in international patent application number WO 97/17351, published May 15, 1997 as 5-HT receptor antagonists.
A subgenus of formula (I) wherein: E is (c); Q is ortho to L; Qxe2x80x94(CR39R40)1xe2x80x94R41 is (CH2)2-2-piperidinyl; R47 is methyl; R42, R43, R3xe2x80x2, and R4xe2x80x2 are hydrogen; L is CONH; P3 is 3-furyl, 2-thienyl, 2-, 3-, and 4-pyridinyl, have been described in U.S. Pat. No. 3,93 1195, published Jan. 6, 1976, and U.S. Pat. No. 4,000,143, published Dec. 28, 1976, and reported to have antiserotonin activity.
A subgenus of formula (I) wherein: E is (g); R71 is meta to L; R71 is (C0-2alkyl-1-piperazine); R72 is hydrogen, methyl, hydroxy, C1-4alkoxy, halogen; R73 is hydrogen, hydroxy, methoxy, or fluoro; R1xe2x80x2, and R2xe2x80x2 are hydrogen, methyl, acetyl; R3xe2x80x2 is hydrogen, methyl, nitro, hydroxy, methoxy, or fluoro: R4xe2x80x2 and R5xe2x80x2 are independently hydrogen, methoxy, bromo; L is CONH or NHCO; Ar is (i) or (ii); P1 is phenyl and P2 is attached at the 4-position, or 2,5-furyl, 3,5-furyl, 2,5-thienyl, 3,5-thienyl, 3,6-pyridinyl, 1,4-naphthalenyl, 1,5-naphthalenyl; P2 is 2-furyl, 3-thienyl, 2-, 3-, or 4-pyridinyl, 5-pyrimidinyl, 1,2,4-oxadiazol-3-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, imidazol-1-yl; P3 is 2-, and 3-furyl, 2-thienyl, 3-thienyl, 2,5-thienyl, 3-pyridinyl, 4-quinolinyl; has been described in in EP 533267, published Mar. 24, 1993, GB 2273930, published Jul. 6, 1994; GB 2276164, published Sep. 21, 1994; international patent application number WO 95/04729, published Feb. 16, 1995: international patent application number WO 95/06644, published Mar. 9, 1995; international patent application number WO 98/47885, published Oct. 29, 1998, as 5-HT receptor antagonists.
A compound of formula (I) wherein: E is (g); R71 is meta to L: R71 is (methyl-1-piperazine); R72 is 4-methoxy; R73 is hydrogen: L is CONR6xe2x80x2; R73 and R6xe2x80x2 are xe2x80x94(CH2)2xe2x80x94; Ar is (ii); R4xe2x80x2 and R5xe2x80x2 are independently methoxy or bromo; P3 is 3-thienyl; has been described in international patent application number WO 95/06637, published Mar. 9, 1995 as a 5-HT receptor antagonist.
A subgenus of formula (I) wherein: the basic nitrogen in moiety E may be optionally quaternized with C1-6alkyl or is optionally present as the N-oxide. E is (b). J is CH2. g is 1, 2, or 3. h is 1, 2, or 3. R24, R25, R26, R27, R28, R29, R31, and R32 are hydrogen. R30 is hydrogen or C1-6alkyl. R33 is hydrogen, C1-6alkyl, trifluoromethyl, or halogen. L is CONR8xe2x80x2, or NR9CO. R8xe2x80x2 and R9xe2x80x2 are independently hydrogen or C1-6alkyl. P1 is phenyl. P2 is heteroaryl, wherein heteroaryl is selected from the group consisting of benzimidazolyl, benzofuranyl, benzooxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazoyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl. R1* is hydrogen, R2* is hydrogen or 1, 2, or 3 of hydroxy, cyano, halogen, trifluoromethyl, NR8*COR10*, NR8*CO2R11*, NR25*CONHR25*, NHS(O)0-2R12*, CONR13*R14*, COC1-5alkyl, CO2R24*, C1-6alkoxy, SR29*, SOR30*, SO2R30*, or phenyl. R3* is hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluoromethyl, CONR34*R35*, COC1-5alkyl, CO2R36*, C1-6alkoxy, or phenyl R8*, R13* R14*, R25*, R29*, R34*, R35*, and R36* are independently hydrogen or C6alkyl. R10* is hydrogen C1-6alkyl, or C1-4alkoxyC1-6alkyl. R11* and R30* are independently C1-6alkyl. R12* is C1-6alkyl or phenyl. R24* is hydrogen or C1-6alkyl optionally substituted with one or two of hydroxy or C1-6alkoxy, has been described in WO 98/25604, published Jun. 18, 1998, as chemokine receptor modulators.
A subgenus of formula (I) wherein: the basic nitrogen in moiety E may be optionally quaternized with C1-6alkyl or is optionally present as the N-oxide. E is (b). J is CH2. g is 1, 2, or 3. h is 1, 2, or 3. R24, R25, R26, R27, R28, R29, R31, and R32 are hydrogen. R30 is hydrogen or C1-6alkyl. R33 is hydrogen, C1-6alkyl, trifluoromethyl, or halogen. L is CH2NH. P1 and P3 are heteroaryl, wherein heteroaryl is selected from the group consisting of benzimidazolyl, benzofuranyl, benzooxazolyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, quinolyl, thiadiazolyl, thiazolyl, thienyl or triazolyl, P2 is phenyl. R1* and R2* are hydrogen. R3* and R5* are hydrogen or 1 or 2 of hydroxy, cyano, halogen, trifluoromethyl, CONR34*R35*, COC1-5alkyl, CO2R36*, C1-6alkoxy, or phenyl. R4* is hydrogen or 1 of hydroxy, cyano, halogen, trifluoromethyl, NR8*COR10*, NR8*CO2R11*, NR25*CONHR25*, NHS(O)0-2R12*, CONR13*R14*, COC1-5alkyl, CO2R24*, C1-6alkoxy, SR29*, SOR30*, SO2R30*, or phenyl, R8*, R13*R14*, R25*, R29*, R34*, R35*, and R36* are independently hydrogen or C1-6alkyl. R10* is hydrogen C1-6alkyl, or C1-4alkoxyC1-6alkyl. R11* and R30* are independently C1-6alkyl. R12* is C1-6alkyl or phenyl. R24* is hydrogen or C1-6alkyl optionally substituted with one or two of hydroxy or C1-6alkoxy, has been described in WO 98/25605, published Jun. 18, 1998, as chemokine receptor modulators.
Formulation of Pharmaceutical Compositions
The pharmaceutically effective compounds of this invention (and the pharmaceutically acceptable salts thereof) are administered in conventional dosage forms prepared by combining a compound of this invention (xe2x80x9cactive ingredientxe2x80x9d) in an amount sufficient to treat COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection, (xe2x80x9cCCR5-mediated disease statesxe2x80x9d) with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1000 mg. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
The active ingredient may also be administered topically to a mammal in need of treatment or prophylaxis of CCR5 mediated disease states. The amount of active ingredient required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physician. A suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
By topical administration is meant non-systemic administration and includes the application of the active ingredient externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
The topical formulations of the present invention, both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carrier(s) therefor and optionally any other therapeutic ingredient(s). The carrier(s) must be xe2x80x98acceptablexe2x80x99 in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100xc2x0 C. for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. The basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
The active ingredient may also be administered by inhalation. By xe2x80x9cinhalationxe2x80x9d is meant intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques. The daily dosage amount of the active ingredient administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
In one aspect, this invention relates to a method of treating COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibrotic diseases, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection, all in mammals, preferably humans, which comprises administering to such mammal an effective amount of a CCR5 receptor modulator, in particular, a compound of this invention.
By the term xe2x80x9ctreatingxe2x80x9d is meant either prophylactic or therapeutic therapy. Such compound can be administered to such mammal in a conventional dosage form prepared by combining the compound of this invention with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The compound is administered to a mammal in need of treatment for COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection, in an amount sufficient to decrease symptoms associated with these disease states. The route of administration may be oral or parenteral.
The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or intraperitoneal administration, The subcutaneous and intramuscular forms of parenteral administration are generally preferred, The daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient, The daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient,
It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of this invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques, It will also be appreciated by one of skill in the art that the optimal course of treatment, i,e., the number of doses of the compound given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests,
Methods of Preparation
Compounds of formula (I) are prepared by condensing suitably substituted heteroaryl carboxylic acids and suitably substituted anilines, which are commercially available or synthesized by methods known to the art from commercially available starting materials, using methods known to the art, For example, suitably substituted heteroaryl carboxylic acids, are treated with a suitable reagent, such as thionyl chloride, at a suitable temperature, such as at reflux, to afford heteroaryl carbonyl chlorides, and the acid chlorides are condensed with suitably substituted anilines in the presence of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane, to give compounds of formula (I). Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books, such as xe2x80x9cCompendium of Organic Synthetic Methodsxe2x80x9d, Vol. I-VI (published by Wiley-Interscience).
Specifically, compounds of this invention were prepared according to the methods described herein and by the methods of: U.S. Pat. No. 3,931,195, published Jan. 6, 1976, U.S. Pat. No. 4,000,143, published Dec. 28, 1976, EP 533267, published Mar. 24, 1993; GB 2273930, published Jul. 6, 1994; GB 2276163, published Sep. 21, 1994; GB 2276164, published Sep. 21, 1994; international patent application number WO 95/04729, published Feb. 16, 1995; international patent application number WO 95/06637, published Mar. 9, 1995; international patent application number WO 95/06644, published Mar. 9, 1995; international patent application number WO 97117351, published May 15, 1997; international patent application number WO 98/47885, published Oct. 29, 1998; and international patent application number WO 98/50343, published Nov. 12, 1998.
Compounds of this invention are also prepared using solid-phase chemistry as described herein and using the general method described in international patent application WO 99/01127, published Jan. 14, 1999. As describe in Scheme I, appropriately substituted (2-alkylamino)ethoxy-anilines I-2, such as 3-[2-(diisopropylamino)ethoxy]-4-methoxyaniline, synthesized from commercially available 2-methoxy-5-nitrophenol, I-1, according to the procedures described in WO 99/01127, are reacted with 4-formyl-3,5-dimethoxyphenol-Merrifield resin 1-3 (Boojamra, et al., J. Org. Chem. 1995, 60, 5742) and a suitable reducing agent, such as sodium triacetoxyborohydride, in a suitable solvent, such as dimethylformamide containing 1% acetic acid, to afford I-4. The resin-bound aniline I-4 is condensed with an appropriately substituted heteroaryl carboxylic acid I-5, which are commercially available or synthesized by methods known to the art, using a suitable activating agent, such as N-bromosuccinimide and triphenylphosphine, in a suitable solvent, such as dichloromethane, dimethylformamide and pyridine, to afford I-6. For example, 1-4 is treated with a ten-fold excess of an equimolar mixture of a 3-heteroaryl carboxylic acid, triphenylphosphine and N-bromosuccinimide, in a suitable solvent, such as dichloromethane, after which a ten-fold excess of a suitable base, such as pyridine, is added, and the mixture is gently agitated for a suitable time, for example forty-eight hours, to afford the resin-bound amide 1-6. Optionally, dimethylformamide may be added to the resulting mixture to increase the solubility of the heteroaryl carboxylic acid. Treatment of I-6 with a suitable acid and solvent, such as trifluoroacetic:dichloromethane:water (50:48:2) gives I-7 which are compounds of this invention. 
(a) Cl(CH2)2NR3R4, K2CO3, CH3COCH3; (b) H2, 5% Pd/C, MeOH; (c) Merrifield resin bound aldehyde (3), NaBH(OAc)3, 1% HOAc/DMF; (d) 3-aryl- or heteroarylcarboxylic acid, N-bromosuccinimide, Ph3P, pyridine, CH2Cl2; (e) TFA, CH2Cl2, H2O
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. In the Examples, mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated.